Synthesis of the Selective D₂ Receptor Agonist PNU-95666E from D-Phenylalanine Using a Sequential Oxidative Cyclization Strategy

Compound 1 (PNU-95666E) is a selective and high-affinity agonist at the dopamine D₂ receptor subtype and is of interest as a potential agent for the treatment of Parkinson's disease. Requiring a synthetic route amenable to scale-up, a synthesis of this enantiomerically pure tricyclic compound was developed, starting from D-phenylalanine. Critical to the success of this synthesis were two oxidative nitrogen annulations to provide the tricyclic ring system. A highly efficient reduction with borane-methyl sulfide was used to reduce three different functional groups, a total of six hydrides transferred, with no concomitant racemization, contributing to the synthesis of 1 in eight steps with an overall yield of 26%. The utility of this synthetic route has been demonstrated by the completion this synthesis on multikilogram scale.